Retinoic acid (RA) which is the carboxylic acid form of vitamin A is a nutrient derivative that has been shown to have remarkable biological effects in regulating glucose, fatty acid, cholesterol and amino acid metabolism as well as adipose tissue biology and the energy balance control system. For example studies have shown that in mice, treatment with all trans RA (ATRA) reduces body weight and adiposity independent of changes in food intake and improves glucose tolerance. Additionally, it has also been shown that the ATRA induced body fat loss correlates with an activation of brown adipose tissue along with increased oxidative metabolism and thermogenesis in white adipose tissue. This is also known to be accompanied by an increased level of circulating nonesterified fatty acids which has been interpreted as meaning that fatty acids mobilized from fat stores undergo oxidation either within the adipocytes themselves or in other tissues.
It is thought that RA regulates gene expression predominantly though activation of either the RA receptors (RAR's) which have been found to be activated by ATRA and 9-cis RA or the rexinoid receptors (RXR's). Unline RAR's, RXR is part of a nuclear receptor superfamily that functions as ligand-activated transcription factors. RXR's are heterodimeric partners of many nuclear receptors such as retinoic acid receptors (RAR's), thyroid hormone receptors (T3R's), liver receptors (LXR's) peroxisome proliferator activated receptors (PPAR's) and also forms a homodimer with RXR's themselves. As such activation of these receptors should have a significant impact on gene expression.
By modulating a multitude of transcription factors, retinoic acids regulate several aspects of metabolic diseases such as hyperglycemia, hypertriglyceridemia, hypercholesterolemia, hypertension, muscle fatigue, haemostasis and managing body weight as well as visceral obesity that makes it an attractive target for obesity and diabetes as well as its related indications.
In addition to metabolic homeostasis, retinoic acid plays a vital role in regulating tissue health and regulates inflammatory responses. Indeed RXR agonists have been shown to have a large number of potential biological activities ranging from the treatment of cancer, skin disorders, metabolic diseases, fibrosis, neuro-degenerative diseases, vascular diseases, eye conditions and inflammatory diseases.
The evidence therefore strongly suggests that compounds that are agonists of RXR's would be useful in the treatment of a number of clinical conditions and therefore the search for suitable agonists of RXR is ongoing.
It would be desirable to provide compounds that are agonists of RXR's. These compounds would be expected to be useful in the treatment of conditions that can be treated by activation of these receptors.
It would also be desirable to provide a pharmaceutical composition containing a compound that is an agonist of RXR and a pharmaceutically acceptable excipient, diluent or carrier.
It would yet even further be desirable to provide a method of prevention or treatment of a condition that can be treated by activation of RXR in a mammal